Copper tolerance in bacteria requires the activation of multiple accessory pathways

Abstract

Copper is a required micronutrient for bacteria and an essential cofactor for redoxactive cuproenzymes. Yet, excess copper is extremely toxic, and is exploited as a bacteriocide in medical and biotechnological applications and also by the mammalian immune system. To evade copper toxicity, bacteria not only control intracellular copper homeostasis, but they must also repair the damage caused by excess copper. In this review, we summarize the bacterial cell-wide response to copper toxicity in Enterobacteria. Tapping into the abundant research data on two key organisms, Escherichia coli and Salmonella enterica, we show that copper resistance requires both the direct copper homeostatic response and also the indirect accessory pathways that deal with copper-induced damage. Since patterns of copper response are conserved through the Proteobacteria, we propose a cell-wide view of copper detoxification and copper tolerance that can be used to identify novel targets for copper-based antibacterial therapeutics.

Mechanisms and heterogeneity of mineral use by natural colonies of the cyanobacteriumTrichodesmium

“…First, consistent with the mineralogical profile of the particles, the colonies engaged specific iron uptake mechanisms that prioritized the (Fig. S9D) 29,30 . Evidence also pointed to involvement of putative movement proteins including RTX proteins and the chemotaxis regulator CheY, both enriched in puffs with particles ( Fig.…”

A novel copper-sensing two-component system for activating Dsb genes in bacteria

“…In addition to CusRS, various periplasmic copper-sensing TCSs (e.g., CopRS, PcoRS, and CinRS) have been identified (8,(20)(21)(22)(23), which supports the notion that the bacterial cell envelope is an important target for copper stress (7,24). Indeed, copper can inhibit lipoprotein maturation and causes periplasmic protein misfolding due to the formation of non-native disulfide bonds (7,24,25). In order to evade copper toxicity, therefore, bacteria not only control intracellular copper homeostasis but also must minimize and repair copper-induced damage (7).…”

“…To evade copper toxicity, bacteria must tightly regulate genes involved in the copper homeostasis (7,8), gathering information through various cytoplasmic Cusensing one-component systems (i.e., CueR, CsoR, and CopY) and periplasmic Cusensing two-component systems (TCSs) (i.e., CusRS, CopRS, PcoRS, and CinRS) (7-9).…”

“…In the archetypical Escherichia coli TCS CusRS, Cu + binding to the periplasmic loop of HK CusS promotes its autophosphorylation, and the subsequent phosphorylation of its cognate RR CusR, which then activate the transcription of cusCFBA genes encoding proteins for the Cu + efflux pump CusCFBA to ameliorate copper toxic effects (14)(15)(16)(17)(18)(19). In addition to CusRS, various periplasmic copper-sensing TCSs (e.g., CopRS, PcoRS, and CinRS) have been identified (8,(20)(21)(22)(23), which supports the notion that the bacterial cell envelope is an important target for copper stress (7,24). Indeed, copper can inhibit lipoprotein maturation and causes periplasmic protein misfolding due to the formation of non-native disulfide bonds (7,24,25).…”

“…Indeed, copper can inhibit lipoprotein maturation and causes periplasmic protein misfolding due to the formation of non-native disulfide bonds (7,24,25). In order to evade copper toxicity, therefore, bacteria not only control intracellular copper homeostasis but also must minimize and repair copper-induced damage (7).…”